Data documento
13/03/2025

Título
Molecular profile of driver genes in lung adenocarcinomas of Brazilian patients who have never smoked: implications for targeted therapies

Autor(es)
Rodrigo de Oliveira Cavagna - Flávia Escremim de Paula - Gustavo Noriz Berardinelli - Murilo Bonatelli - Iara Santana - Eduardo Caetano Albino da Silva - Gustavo Ramos Teixeira - Beatriz Garbe Zaniolo - Flávio Augusto Ferreira da Silva - Carlos Eduardo Baston Silva - Josiane Mourão Dias - Marcela Gondim Borges Guimarães - Camila Pinto Barone - Alexandre Arthur Jacinto - Rachid Eduardo Noleto da Nóbrega Oliveira - José Elias Miziara - Pedro De Marchi - Miguel A. Molina-Vila - Letícia Ferro Leal - Rui Manuel Reis

Palavras chave
lung adenocarcinoma; molecular profile; driver mutations; never smoker; Latin America.

Resumo
Introduction: Lung cancer in never-smoker (LCINS) patients accounts for 20% of lung cancer cases, and its biology remains poorly understood, particularly in genetically admixed populations. We elucidated the molecular profile of driver genes in Brazilian LCINS. Methods: The mutational and gene fusion status of 119 lung adenocarcinomas from self-reported never-smoker patients, was assessed using targeted sequencing (NGS), nCounter, and immunohistochemistry. A panel of 46 ancestry-informative markers determined patients’ genetic ancestry. Results: The most frequently mutated gene was EGFR (49.6%), followed by TP53 (39.5%), ALK (12.6%), ERBB2 (7.6%), KRAS (5.9%), PIK3CA (1.7%), and less than 1% alterations in RET, NTRK1, MET∆ex14, PDGFRA, and BRAF. Except for TP53 and PIK3CA, all other alterations were mutually exclusive. Genetic ancestry analysis revealed a predominance of European (71.1%), and a higher African ancestry was associated with TP53 mutations. Conclusion: Brazilian LCINS exhibited a similar molecular profile to other populations, except the increased ALK and TP53 alterations. Importantly, 73% of these patients have actionable alterations that are suitable for targeted treatments.

Citação
Cavagna RO, Escremim de Paula F, Berardinelli GN, Bonatelli M, Santana I, Albino da Silva EC, Teixeira GR, Zaniolo BG, Mourão Dias J, Ferreira da Silva FA, Baston Silva CE, Guimarães MGB, Barone CP, Jacinto AA, Noleto da Nóbrega Oliveira RE, Miziara JE, De Marchi P, Molina-Vila MA, Leal LF, Reis RM. Oncologist. 2024 Oct 3;29(10):e1419-e1424. doi: 10.1093/oncolo/oyae129. PMID: 38944844

Data documento
19/03/2025

Título
PD-L1 expression and microsatellite instability (MSI) in cancer of unknown primary site

Autor(es)
João Neif Antonio Junior - Daniel D Almeida Preto - Maria Eduarda Zanatta Neder Lazarini - Marcos Alves de Lima - Murilo Bonatelli - Gustavo Noriz Berardinelli - Vinicius Duval da Silva - Céline Pinheiro - Rui Manuel Reis - Flavio Mavignier Cárcano.

Palavras chave
Immune checkpoint proteins; Immunotherapy; Microsatellite instability; Neoplasms; Unknown primary.

Resumo
Background: Cancer of unknown primary site (CUP) is a heterogeneous group of tumors for which the origin remains unknown. Clinical outcomes might be influenced by regulatory processes in its microenvironment. Microsatellite instability (MSI) is a predictive biomarker for cancer immunotherapy and its status, as well as co-occurrence with PD-L1 expression, is poorly evaluated. We aim to evaluate the expression of PD-L1 and the status of MSI in CUP and their possible associations with clinical-pathological features. Methods: The combined positive score (CPS) PD-L1 expression was evaluated by immunohistochemistry. MSI status was assessed using a hexa-plex marker panel by polymerase chain reaction followed by fragment analysis. Results: Among the 166 cases, MSI analysis was conclusive in 120, with two cases being MSI positive (1.6%). PD-L1 expression was positive in 18.3% of 109 feasible cases. PD-L1 expression was significantly associated with non-visceral metastasis and a dominance of nodal metastasis. The median overall survival (mOS) was 3.7 (95% CI 1.6-5.8) months and patients who expressed PD-L1 achieved a better mOS compared to those who did not express PD-L1 (18.7 versus 3.0 months, p-value: < .001). ECOG-PS equal to or more than two and PD-L1 expression were independent prognostic factors in multivariate analysis (2.37 and 0.42, respectively). Conclusion: PD-L1 is expressed in a subset (1/5) of patients with CUP and associated with improved overall survival, while MSI is a rare event. There is a need to explore better the tumor microenvironment as well as the role of immunotherapy to change such a bad clinical outcome.

Citação
unior JNA, Preto DD, Lazarini MEZN, de Lima MA, Bonatelli M, Berardinelli GN, da Silva VD, Pinheiro C, Reis RM, Cárcano FM.Int J Clin Oncol. 2024 Jun;29(6):726-734. doi: 10.1007/s10147-024-02494-3.Epub 2024 Mar 25. PMID: 38528294